SRPIN340

• CAT Number: I002667
• CAS Number: 218156-96-8
• Molecular Formula: C18H18F3N3O
• Molecular Weight: 349.357
• Purity: ≥95%
• Target: SRPK
• Solubility: DMSO: ≥ 42 mg/mL
• Storage: Store at -20C
• IC50: 0.89 uM (SRPK1) [1]
• IUPAC Name: N-[2-piperidin-1-yl-5-(trifluoromethyl)phenyl]pyridine-4-carboxamide
• InChI: InChI=1S/C18H18F3N3O/c19-18(20,21)14-4-5-16(24-10-2-1-3-11-24)15(12-14)23-17(25)13-6-8-22-9-7-13/h4-9,12H,1-3,10-11H2,(H,23,25)
• InChIKey: DWFGGOFPIISJIT-UHFFFAOYSA-N
• SMILES: C1CCN(CC1)C2=C(C=C(C=C2)C(F)(F)F)NC(=O)C3=CC=NC=C3

SRPIN340 is a serine/arginine-rich protein kinase (SRPK)-specific inhibitor with an IC50 value of 0.89 uM (SRPK1); no significant inhibitory activity against more than 140 other kinases.IC50 Value: 0.89 uM (SRPK1) [1]Target: SRPKin vitro: SRPIN340 potently inhibits SRPK1 kinase activity, with a Kivalue of 0.89 μM. SRPIN340 inhibits SR phosphorylation by SRPK in Flp-In293 cells and promotes degradation of SRp75 in a dose-dependent manner (Fig. 4). Thus, because retention of SRp75 is necessary for HIV expression, SRPIN340 emerges as a potential inhibitor of HIV production. SRPIN340 (40 μM) rescues Vero cells from the cytopathic effect of Sindbis virus. The SRPIN340 IC50 for Sindbis virus propagation was 60 μM [1]. SRPIN340, suppressed in a dose-dependent fashion expression of a hepatitis C virus (HCV) subgenomic replicon and replication of the HCV-JFH1 clone in vitro. The inhibitory effects were not associated with antiproliferative or nonspecific cytotoxic effects on the host cells. Overexpression of SRPK1 or SRPK2 resulted in augmentation of HCV replication, while small interfering RNA (siRNA) knockdown of the SRPKs suppressed HCV replication significantly [2]. SRPIN340 inhibited CNV formation in a dose-dependent manner. Compared with the vehicle, SRPIN340 significantly decreased the protein levels of VEGF, MCP-1, ICAM-1, and consequently inhibited macrophage infiltration. Furthermore, SRPIN340 suppressed the gene expression levels of total Vegf and exon 8a-containing Vegf isoforms [3].in vivo: No adverse effects were observed when SRPIN340 was orally administrated to rats, even at the highest SRPIN340 dose (2,000 mg/kg). In addition, no abnormalities in chromosomal structure and chromosome number were observed when SRPIN340 was administrated to CHO cells in the culture medium at the highest SRPIN340 dose (5 mg/ml) for 24 h [1].Toxicity: The rudimentary toxicity data available for SRPIN340 is promising with respect to the potential for use of this compound as a therapeutic. No adverse effects were observed when SRPIN340 was orally administrated to rats, even at the highest SRPIN340 dose (2,000 mg/kg). In addition, no abnormalities in chromosomal structure and chromosome number were observed when SRPIN340 was administrated to CHO cells in the culture medium at the highest SRPIN340 dose (5 mg/ml) for 24 h [1].Clinical trial:

Reference

1:PLoS One. 2015 Aug 5;10(8):e0134882. doi: 10.1371/journal.pone.0134882. eCollection 2015. Potential Antileukemia Effect and Structural Analyses of SRPK Inhibition by N-(2-(Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl)Isonicotinamide (SRPIN340).Siqueira RP,Barbosa Éde A,Polêto MD,Righetto GL,Seraphim TV,Salgado RL,Ferreira JG,Barros MV,de Oliveira LL,Laranjeira AB,Almeida MR,Júnior AS,Fietto JL,Kobarg J,de Oliveira EB,Teixeira RR,Borges JC,Yunes JA,Bressan GC, PMID: 26244849 PMCID: PMC4526641 DOI: 10.1371/journal.pone.0134882 Abstract: Dysregulation of pre-mRNA splicing machinery activity has been related to the biogenesis of several diseases. The serine/arginine-rich protein kinase family (SRPKs) plays a critical role in regulating pre-mRNA splicing events through the extensive phosphorylation of splicing factors from the family of serine/arginine-rich proteins (SR proteins). Previous investigations have described the overexpression of SRPK1 and SRPK2 in leukemia and other cancer types, suggesting that they would be useful targets for developing novel antitumor strategies. Herein, we evaluated the effect of selective pharmacological SRPK inhibition by N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) on the viability of lymphoid and myeloid leukemia cell lines. Along with significant cytotoxic activity, the effect of treatments in regulating the phosphorylation of the SR protein family and in altering the expression of MAP2K1, MAP2K2, VEGF and FAS genes were also assessed. Furthermore, we found that pharmacological inhibition of SRPKs can trigger early and late events of apoptosis. Finally, intrinsic tryptophan fluorescence emission, molecular docking and molecular dynamics were analyzed to gain structural information on the SRPK/SRPIN340 complex. These data suggest that SRPK pharmacological inhibition should be considered as an alternative therapeutic strategy for fighting leukemias. Moreover, the obtained SRPK-ligand interaction data provide useful structural information to guide further medicinal chemistry efforts towards the development of novel drug candidates.